Disordered methionine/homocysteine metabolism in premature vascular disease. Its occurrence, cofactor therapy, and enzymology.

Dudman, Nicholas P.B.; Wilcken, D. E. L.; Wang, J.; Lynch, Jodi; Macey, D.J.; Lundberg, Peter

doi:10.1161/01.atv.13.9.1253

Cited by 185 publications

(63 citation statements)

References 23 publications

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“…Our observations are consistent with those of Dudman et al, 30 who reported that the majority of patients with premature vascular disease and impaired homocysteine metabolism have normal levels of methionine synthase. In another report, the significant correlation between homocysteine and 5-methyltetrahydrofolate, a substrate for methionine synthase whose metabolism is regulated by MTHFR, was reported in patients with coronary artery disease.…”

Section: Discussionsupporting

confidence: 93%

Polymorphism of the Methionine Synthase Gene

Morita

Kurihara

Sugiyama

et al. 1999

ATVB

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Abstract-Methionine synthase and 5,10-methylenetetrahydrofolate reductase (MTHFR) sequentially catalyze the remethylation of homocysteine to methionine. A point mutation in the encoding region of the methionine synthase gene, which results in substitution of an aspartic acid for a glycine residue (D919G), has been identified in patients of the cblG genetic complementation group; these patients exhibit significantly decreased methionine synthase activity. Nevertheless, the D919G mutation has also been reported to be common in the general population. In this study, we analyzed the distribution of methionine synthase D/G polymorphism in the Japanese population and examined the extent to which it is associated with altered homocysteine metabolism and late-onset vascular diseases. We studied 215 patients with coronary artery disease, 251 patients with histories of ischemic stroke, and 257 control subjects. The methionine synthase genotype was analyzed by polymerase chain reaction followed by HaeIII digestion; allele frequencies for the D919G variant of the enzyme proved to be similar in all 3 subject groups (control subjects, 0.17; coronary artery disease patients, 0.17; and ischemic stroke patients, 0.19). Furthermore, in patients with ischemic stroke, plasma levels of homocyst(e)ine and folate were similar, irrespective of methionine synthase genotype. Thus, the methionine synthase D919G mutation was found to be common in the Japanese general population, and it appears unlikely that this polymorphism has a major effect on homocysteine metabolism and/or the onset of vascular diseases. Key Words: homocysteine Ⅲ methionine synthase Ⅲ methylenetetrahydrofolate reductase Ⅲ genetics R ecent reports indicate that even modest increases in plasma homocyst(e)ine levels can lead to an increased risk of occlusive vascular disease. [1][2][3][4][5][6][7][8][9] Homocysteine is a sulfur amino acid generated as an intermediate product in methionine metabolism and occurs at the intersection of 2 metabolic pathways, remethylation and transsulfuration. These pathways are known to be regulated by 3 key enzymes: cystathionine ␤-synthase, 5-methyltetrahydrofolate:homocysteine methyltransferase (methionine synthase), and 5,10-methylenetetrahydrofolate reductase (MTHFR), as well as by the cofactors folate, vitamin B 6 , and vitamin B 12 . Many studies, 10 -14 including ours, have shown that differences in the plasma levels of homocyst(e)ine and folate are associated with variation in the MTHFR genotype, as reported by Frosst et al. 15 Moreover, this MTHFR gene polymorphism, which is associated with a predisposition for elevated plasma concentrations of homocyst(e)ine, has been reported to represent a genetic risk factor for occlusive vascular diseases, although it remains controversial. 11-14,16 -21 Methionine synthase catalyzes the remethylation of homocysteine to methionine in a methylcobalamin-dependent reaction, and a deficiency of methionine synthase activity results in hyperhomocysteinemia. Indeed, homocystinuria, a rare autosomal ...

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Section: Discussionsupporting

confidence: 93%

Polymorphism of the Methionine Synthase Gene

Morita

Kurihara

Sugiyama

et al. 1999

ATVB

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“…Brattström et al (1990) indicated that supplementation with 240 mg of vitamin B 6 for 2-week decreased the mean post methionine load increase in the homocysteine concentration by 26% (Po0.001) in 20 very early-onset vascular disease patients. Other studies also showed similar results with a pyridoxine supplement at a dose of 20-100 mg (Dudman et al, 1993;Ubbink et al, 1996). Vitamin B 6 , therefore, mainly affects homocysteine only in the postprandial state.…”

Section: Discussionsupporting

confidence: 56%

Folic acid and vitamin B12 are more effective than vitamin B6 in lowering fasting plasma homocysteine concentration in patients with coronary artery disease

et al. 2004

Eur J Clin Nutr

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Objective: To investigate whether vitamin B 6 supplementation had a beneficial effect on lowering fasting plasma homocysteine concentrations in coronary artery disease (CAD) patients. Design: A single-blind intervention study. Setting: The study was performed at the Taichung Veterans General Hospital, the central part of Taiwan. Subjects: A total of 50 subjects were identified by cardiac catheterization to have at least 70% stenosis of one major coronary artery. In all, 42 patients successfully completed this study. Interventions: Patients were randomly assigned to one of five groups and treated with a daily dose of placebo (n ¼ 8), 5 mg vitamin B 6 (n ¼ 8), 10 mg vitamin B 6 (n ¼ 8), 50 mg vitamin B 6 (n ¼ 9), or 5 mg folic acid combined with 0.25 mg vitamin B 12 (n ¼ 9) for 12 weeks. Main outcome measures: Nutrient intakes were recorded by using 24-h diet recalls when patients returned to the cardiology clinic before the intervention (week 0) and at week 12. Vitamin B 6 status was assessed by direct measures (plasma pyridoxal 5 0 -phosphate) and indirect measures (erythrocyte alanine and aspartate aminotransaminase activity coefficient). Fasting plasma homocysteine, serum folic acid, and vitamin B 12 were measured. Results: Fasting plasma homocysteine concentration did not respond to high or low doses of vitamin B 6 when compared with a placebo treatment after 12 weeks of supplementation. The mean fasting plasma homocysteine concentration, however, decreased significantly after 12 weeks of folic acid combined with vitamin B 12 supplementation (P ¼ 0.047). Further, within group, mean fasting plasma homocysteine concentration was nonsignificantly increased by 25.5, 16.2, and 18.3% in placebo, 10 mg/day and 50 mg/day vitamin B 6 supplemented groups, respectively; whereas folic acid combined with vitamin B 12 supplementation significantly reduced fasting plasma homocysteine concentration by 32% (Po0.001). Conclusions: Our results indicate that vitamin B 6 supplementation alone is less effective than folic acid combined with vitamin B 12 in lowering plasma homocysteine concentrations in CAD patients.

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“…This may be due to differences in, or imprecision of, the assay procedure. Some authors determined free homocysteine (homocysteine-cysteine mixed disulfide and homocystine) [7,8,13], while others determined total (free and protein-bound) homocysteine [9,11,12], or both [lo]. Recently, we observed clearly elevated total plasma homocysteine concentrations, fasting as well as after methionine loading, in postmenopausal women when compared to premenopausal women [24].…”

Section: Discussionmentioning

confidence: 99%

Hormone replacement therapy may reduce high serum homocysteine in postmenopausal women

Mooren

Wouters

Blom

et al. 1994

Eur J Clin Investigation

147

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Abstract. In a prospective study we investigated the possible changes in fasting serum total homocysteine concentrations during continuous micronized 17P-oestradiol, 2 mg daily, in combination with cyclic dydrogesterone, lOmg daily during the first 14 days of each 28 day cycle, in 21 healthy non-hysterectomized postmenopausal women. During the first six cycles mean serum homocysteine decreased by 1O.!I0/0 (P = 0.01 3), after which no further significant changes were found during the 2 years of treatment. A 16.9% decrease ( P = 0.017; n = 8) was found in women with high homocysteine concentrations, while in women with low homocysteine concentrations (n = 13) no significant changes were observed. The observed decrease in high homocysteine concentrations in postmenopausal women may in part contribute to the decreased risk of developing cardiovascular disease during hormone replacement therapy.

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Disordered methionine/homocysteine metabolism in premature vascular disease. Its occurrence, cofactor therapy, and enzymology.

Cited by 185 publications

References 23 publications

Polymorphism of the Methionine Synthase Gene

Polymorphism of the Methionine Synthase Gene

Folic acid and vitamin B12 are more effective than vitamin B6 in lowering fasting plasma homocysteine concentration in patients with coronary artery disease

Hormone replacement therapy may reduce high serum homocysteine in postmenopausal women

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